Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies

Hanyin Cheng, Avinash V. Dharmadhikari, Sylvia Varland, Ning Ma, Deepti Domingo, Robert Kleyner, Alan F. Rope, Margaret Yoon, Asbjørg Stray-Pedersen, Jennifer E. Posey, Sarah R. Crews, Mohammad K. Eldomery, Zeynep Coban Akdemir, Andrea M. Lewis, Vernon R. Sutton, Jill A. Rosenfeld, Erin Conboy, Katherine Agre, Fan Xia, Magdalena WalkiewiczMauro Longoni, Frances A. High, Marjon A. van Slegtenhorst, Grazia M.S. Mancini, Candice R. Finnila, Arie van Haeringen, Nicolette den Hollander, Claudia Ruivenkamp, Sakkubai Naidu, Sonal Mahida, Elizabeth E. Palmer, Lucinda Murray, Derek Lim, Parul Jayakar, Michael J. Parker, Stefania Giusto, Emanuela Stracuzzi, Corrado Romano, Jennifer S. Beighley, Raphael A. Bernier, Sébastien Küry, Mathilde Nizon, Mark A. Corbett, Marie Shaw, Alison Gardner, Christopher Barnett, Ruth Armstrong, Karin S. Kassahn, Anke Van Dijck, Geert Vandeweyer

Research output: Contribution to journalArticlepeer-review


N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.

Original languageEnglish
JournalAmerican Journal of Human Genetics
Publication statusAccepted/In press - Jan 1 2018


  • autism
  • congenital heart defects
  • intellectual disability
  • N-terminal acetylation (NTA)
  • N-terminal acetyltransferases (NATs)
  • NAA10
  • NAA15
  • NatA complex
  • neurodevelopmental disorder
  • Ogden syndrome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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